FDA Guideline for the submission of “Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products”

21 CFR Part 211 — Current Good Manufacturing Practices for Finished Pharmaceuticals

Purpose:

Environmental control is designed to prevent microbiological contamination of sterile products.

Environmental monitoring is designed to detect microbiological contamination in aseptic processing areas.

Scope: Environmental control and monitoring is a required part of aseptic processing, i.e. where “terminal” sterilization is not possible. Terminal sterilization means the finished drug product is sterilized at the last step of the process via heat, radiation or other. Many pharmaceuticals and most biologics do not tolerate terminal sterilization, thus the importance of aseptic processing.

Control Considerations:

Air particle count: maintaining air particle counts is critical to aseptic processing, because particles themselves can be harmful, and likely carry microorganisms.

Cleanroom design: for the aseptic core (where critical aseptic process steps occur, e.g. where product is open to the environment) the FDA recommends class 100. The core should surrounded by class 1,000 or class 10,000 areas.

Air pressure differentials: the FDA recommends a 10-15 Pascal pressure differential between rooms of differing classification, with the higher pressure in higher-class rooms, so that air naturally flows outward to the lower class rooms.

HEPA filtration: High Efficiency Particulate Air (HEPA) filters should be used in class 100 rooms to aid in particle removal

Equipment: should be cleanable and non-shedding. Stainless steel is the preferred material of construction for equipment surfaces.

Process design: processes should be designed with minimizing contaminate risks in mind (e.g. don’t force operators to reach over open product)

Process Validation: media runs should be performed to demonstrate the process can run aseptically

Monitoring Considerations:

Air quality measurements should look at viable and nonviable particulate levels